Manchester United arrive at the Boleyn Ground for Saturday's televised evening kick-off having been soundly beaten by Liverpool in their last Barclays Premier League outing.
The champions face a battle to get into the top-four, currently lying in seventh place in the table and West Ham United will be hoping to further dent their European aspirations by inflicting their tenth defeat of the campaign.
Here, whufc.com takes a look back at six memorable wins against the Red Devils.
West Ham United 4-0 Manchester United
Carling Cup fifth round
30 November 2010
From a season of few highlights for the Hammers, this thumping victory over a Manchester United side including the likes of Jonny Evans, Ryan Giggs and Javier Hernandez was certainly one of them.
Jonathan Spector had never hit the back of the net during his four years at the Boleyn Ground, but he broke that duck in style by notching a first half brace.
That gave the Hammers a commanding interval position, and they built on that further with two Carlton Cole goals in the second half to secure a memorable 4-0 win.
Avram Grant's side would go on to reach the semi-finals of this competition before bowing out to Birmingham City, whilst in the league they suffered the heartbreak of relegation.
Jonathan Spector scores against Manchester United
West Ham United 2-1 Manchester United
Premier League
29 December 2007
The Hammers' last league success over Manchester United came as a late Christmas present in 2007.
West Ham left it late to inflict defeat on a Red Devils outfit who would go on to secure the Premier League title at the end of the season.
The visitors led through a 14th-minute Cristiano Ronaldo strike for the vast majority of this contest, but the Portuguese missed a penalty before two defenders got in on the act in the final 13 minutes to wrest the points away.
Anton Ferdinand scored West Ham's equaliser, before Matt Upson's 82nd-minute header had the 34,966 Boleyn Ground crowd bouncing.
West Ham United 1-0 Manchester United
Premier League
17 December 2006
West Ham's 1-0 victory over Manchester United in December 2006 provided part one of a double, which ultimately secured their Premier League safety.
The Hammers came into this fixture having lost on their last three starts and few would have given them a chance of ending that run. But they tore up the form book to secure all three points thanks to Nigel Reo-Coker's 75th-minute goal.
Despite the victory the east Londoners were still in the relegation zone and had to wait until a win over Bolton in their penultimate game to climb out of the bottom three. Carlos Tevez' solitary goal at Old Trafford on the final day made sure of survival.
Nigel Reo-Coker celebrates his winner against the Red Devils
West Ham United 1-0 Manchester United
Division One
25 April 1992
The Hammers may have been heading through the relegation trap door ahead of the imminent arrival of the Premier League, but they were still able to dent Manchester United's title ambitions at a crucial stage of the season.
Ferguson's side were aiming to pip Leeds United to the title, but they were ultimately to come up short - not helped by this defeat in east London.
Kenny Brown scored the only goal of the game and despite a final day win over Nottingham Forest, the Hammers found themselves having to face up to the prospect of second tier football in 1992/93.
West Ham United 3-0 Manchester United
Division One
1 January 1972
The Hammers got 1972 off to a perfect start with this 3-0 romp against Manchester United on New Year's Day.
West Ham were bobbing along in mid-table and by beating the Red Devils, they completed a fine Christmas period having won away at Tottenham Hotspur in their previous game.
A Geoff Hurst penalty, plus goals from Clyde Best and Bryan Robson secured both points in front of 41,892 at the Boleyn Ground.
West Ham United 2-1 Manchester United
FA Cup third round
25 February 1911
West Ham's first-ever home win against Manchester United came before the club had even entered the Football League.
Syd King's team were members of the Southern League First Division, whilst the Red Devils were in the top flight of the Football League. But the Hammers were the winners on this occasion thanks to goals from Danny Shea and Thomas Caldwell to take their FA Cup run to the fourth round.
Blackburn Rovers stood in their way and the Hammers bowed out by the odd goal in five before securing a fifth-place finish in the Southern League.